Non-small cell lung cancer in never smokers: a clinical
entity to be identified
Ilka Lopes Santoro, Roberta Pulcheri Ramos, Juliana Franceschini, Sergio Jamnik, Ana Luisa Godoy
Federal University of Sa ˜o Paulo, Respiratory Division, Sa ˜o Paulo/SP, Brazil.
OBJECTIVES: It has been recognized that patients with non-small cell lung cancer who are lifelong never-smokers
constitute a distinct clinical entity. The aim of this study was to assess clinical risk factors for survival among never-
smokers with non-small cell lung cancer.
METHODS: All consecutive non-small cell lung cancer patients diagnosed (n=285) between May 2005 and May 2009
were included. The clinical characteristics of never-smokers and ever-smokers (former and current) were compared
using chi-squared or Student’s t tests. Survival curves were calculated using the Kaplan-Meier method, and log-rank
tests were used for survival comparisons. A Cox proportional hazards regression analysis was evaluated by adjusting
for age (continuous variable), gender (female vs. male), smoking status (never- vs. ever-smoker), the Karnofsky
Performance Status Scale (continuous variable), histological type (adenocarcinoma vs. non-adenocarcinoma), AJCC
staging (early vs. advanced staging), and treatment (chemotherapy and/or radiotherapy vs. the best treatment
RESULTS: Of the 285 non-small cell lung cancer patients, 56 patients were never-smokers. Univariate analyses
indicated that the never-smoker patients were more likely to be female (68% vs. 32%) and have adenocarcinoma
(70% vs. 51%). Overall median survival was 15.7 months (95% CI: 13.2 to 18.2). The never-smoker patients had a
better survival rate than their counterpart, the ever-smokers. Never-smoker status, higher Karnofsky Performance
Status, early staging, and treatment were independent and favorable prognostic factors for survival after adjusting
for age, gender, and adenocarcinoma in multivariate analysis.
CONCLUSIONS: Epidemiological differences exist between never- and ever-smokers with lung cancer. Overall
survival among never-smokers was found to be higher and independent of gender and histological type.
KEYWORDS: Lung neoplasm; Non-small cell lung cancer; Adenocarcinoma; Never-smoker; Smoking.
Santoro IL, Ramos RP, Franceschini J, Jamnik S, Fernandes ALG. Non-small cell lung cancer in never smokers: a clinical entity to be identified. Clinics.
Received for publication on March 4, 2011; First review completed on March 30, 2011; Accepted for publication on July 12, 2011
Tel.: 55 11 5549-1830
Lung cancer remains the leading cause of cancer mortality,
accounting for more deaths than breast, colon, and prostate
cancer combined. Smoking was established as a risk factor
for lung cancer in the early 1950s.1-3Moreover, smoking is
associated with both lung cancer carcinogenesis and the
prognosis of lung cancer patients.4Due to the overwhelming
etiological role of tobacco smoking, lung cancer is mainly
considered a smoking-related disease; consequently, the
never-smoker population is usually under-represented in
lung cancer studies.5Only recently has attention turned
toward the small number of never-smokers with this disease.
The proportion of never-smokers with lung cancer is
expected to increase in parallel with successful smoking
prevention and smoking cessation programs. Although
the incidence of lung cancer may be increasing among
never-smoker patients, it is unclear whether this increase
represents are real increase in the lung cancer incidence
among never-smokers or arises from the increasing pre-
valence of never-smokers in the general population.6
It is noteworthy that differences in epidemiological
characteristics and histological subtypes between smokers
and never-smokers have been demonstrated, especially
among Asian patients.7,8This suggests that the pathogenesis
of non-small cell lung cancer (NSCLC) in never-smokers
might be different than in smokers. It was recently demon-
strated that a subgroup of patients with NSCLC exhibits a
specific activating mutation in the epidermal growth factor
such as tyrosine kinase inhibitor drugs, and overall survival.9
There is limited literature regarding never-smoker lung
cancer patients in the Western hemisphere, especially in
Copyright ? 2011 CLINICS – This is an Open Access article distributed under
the terms of the Creative Commons Attribution Non-Commercial License (http://
creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-
commercial use, distribution, and reproduction in any medium, provided the
original work is properly cited.
No potential conflict of interest was reported.
CLINICS 2011;66(11):1873-1877 DOI:10.1590/S1807-59322011001100005
Brazil. The aim of this study was to assess the epidemio-
logical characteristics of never-smoker patients with lung
cancer, focusing on clinical risk factors and survival.
The study described here was a prospective cohort study
conducted between May 2005 and May 2009 using an
electronic database. All consecutive patients with patholo-
gically proven NSCLC who presented at our outpatient lung
cancer clinic were eligible. The Institutional Review Board
of our center approved this study. Patient consent was
obtained for entry into the database.
Data were collected at diagnosis as part of routine clinical
practices using a structured data collection format. The
selected epidemiological characteristics included age, gen-
der, and ethnicity.
NSCLC was further divided into three major histological
subtypes: squamous cell carcinoma (SCC), adenocarcinoma
and other types of carcinoma (large-cell carcinoma, poorly
or undifferentiated carcinoma and not otherwise specified
NSCLC). The vast majority of the lung specimens that were
used for diagnosis were bronchial biopsies, and immuno-
histochemistry was employed to better identify the histolo-
gical types when required. The American Joint Committee
on Cancer (AJCC) staging system (sixth edition) was
applied, and for analysis purposes, disease stage was
categorized into two groups: early disease (Stages Ia to
IIIa) and advanced disease (Stages IIIb and IV); moreover,
among Stage IV patients, the database included whether
metastases were intra- or extrathoracic.
Weight loss, comorbidity, the Karnofsky Performance
Status Scale, smoking status and treatments were docu-
mented. Weight loss was categorized into two groups: 10%
or more and less than 10%.
Comorbidities included one or more of the following
conditions: hypertension, ischemic heart disease, diabetes
mellitus, chronic obstructive pulmonary disease, asthma,
and pulmonary tuberculosis sequelae.
Smoking status was classified into two levels: ever-smoker
and never-smoker. Patients with any history of smoking
(current and former smokers) were classified as ever-
in pack-years. Never-smokers were defined as thosewhohad
never smoked in the past. Data related to passive exposure to
environmental tobacco smoke and cooking fumes were not
consistently available. Consequently, for the purpose of
analysis, the never-smoker category did not account for
Treatment status was stratified into two categories:
treated (surgery, chemotherapy, or/and irradiation) and
best treatment support.
The date of the last follow-up or of death was collected for
each patient. Overall survival was measured from the date
of histological diagnosis to the date of death or the date that
the patient was last known to be alive for censored
Differences between the never- and ever-smokers were
compared using the chi-squared test for categorical vari-
ables and Student’s t-test for continuous data, as were the
differences between the two genders within the group of
Survival curves and the five-year survival rates were
calculated according to the Kaplan-Meier method, while a
log-rank test was used to assess the differences in survival
between the groups. A multivariate analysis (Cox propor-
tional hazard regression) was evaluated by adjusting for
known prognostic factors and potential confounders. The
number of independent variables (factors) was limited by
the occurrence of the event (death). The factors considered
for inclusion were gender (female vs. male), smoking status
(never- vs. ever-smoker), histological type (adenocarcinoma
vs. non-adenocarcinoma), AJCC stage (early vs. advanced
staging), and treatment (chemotherapy and/or radiother-
apy vs. the best treatment support). The age at diagnosis
and the Karnofsky Performance Status Scale were adjusted
as continuous variables in the Cox regression model.
Statistical analyses were performed using IBM’s Statistical
Package for the Social Sciences, version 19.0. All hypothesis
tests were two-tailed, and the level of significance was set
Two hundred eighty-five NSCLC patients diagnosed
between May 2005 and May 2009 were included in our
analysis. The majority were ever-smokers (76%). The
median tobacco exposure was 41 pack-years (range: 1 to
210 pack-years). Among the never-smokers (56 patients),
there were significantly more women (68%) and adenocar-
cinomas (70%). There were no significant differences
between never- and ever-smokers with regard to age, the
Karnofsky Performance Status Scale, weight loss, ethnicity,
comorbidities, AJCC stage, and patient treatment. The
majority of the patients presented with advanced disease,
although no significant difference in the proportion of
advanced disease or extrathoracic disease was observed
between the groups (Table 1).
Supplementary analyses were completed for the never-
smoker group to examine the behavior of the variables
analyzed above according to gender. The patients of both
genders were similar with respect to age, the Karnofsky
Performance Status Scale, the proportion of histological
types, weight loss, comorbidities, extrathoracic metastasis,
and patient treatment. However, female never-smokers
exhibited a greater proportion of Stages IIIb and IV than
their male counterparts (Table 2).
The overall five-year survival rates of never-smokers
and ever-smokers were significantly different (p=0.049)
(Figure 1). The median overall survival was 15.7 months
(95% CI: 13.2 to 18.2). The median survival time was 14.9
months (95% CI: 12.9 to 16.9 months) for ever-smokers and
22.1 months (95% CI: 9.5 to 34.6 months) for never-smokers.
To complement the survival study, a multivariate analysis
was conducted using the Cox proportional hazard model.
Being a never-smoker (vs. an ever-smoker), a higher
Karnofsky Performance Status, early staging and treatment
(vs. the best treatment support) were independent and
favorable prognostic factors for overall survival after
adjusting for age, gender, and adenocarcinoma (vs. non-
adenocarcinoma) (Table 3).
Moreover, a subgroup analysis of never-smokers revealed
that the survival of the never-smoker-population did not
show any influence of female gender (vs. male) or adeno-
carcinoma (vs. non-adenocarcinoma) on the Cox regression
[-2log likelihood=105,803; chi-squared=2,027; p=0.363).
Non-small cell lung cancer in never-smokers
Santoro IL et al.
Our main finding was that never-smokers had better five-
year survival rates than ever-smokers. This confirms the
results of the other studies, which have shown survival
benefits associated with a never-smoking status in NSCLC
patients. Never-smoking status has been reported as an
independent predictor of improved survival at five years
(16% for current smokers, 23% for never-smokers),10and a
poorer survival outcome in patients with a history of
However, there is controversy regarding this finding in
the current literature. Another study did not find differ-
ences in survival between NSCLC patients stratified
according to their smoking status.11
In our study the presence of comorbidities did not differ
between ever or never-smokers, although it has been described
with tobacco-related disease. Conversely, in other studies the
presence of comorbidities justified the worst survival among
lung cancer patients.12
For a more comprehensive analysis, we performed a Cox
proportional hazards regression adjusted for known prog-
nostic factors. This multivariate analysis also confirmed that
never-smokers exhibited a decreased risk of dying. As
Table 1 - Characteristics of NSCLC patients grouped according to their smoking status at diagnosis.
Age mean (SD)
Karnofsky Performance Status mean (SD)
Female, n (%)
Histological type, n (%)
Weight loss $10%, n (%)
Staging, n (%)
IIIb to IV (advanced disease)
Extrathoracic metastasis, n (%)
Treatment, n (%)
Best support treatment
n=number of patients; SD=standard deviation.
Table 2 - Subject characteristics of never-smoker patients
Age mean (SD)
Karnofsky performance status mean
Histological type n (%)
$10% Weight loss n (%)
Comorbidity n (%)
Staging n (%)
IIIb to IV
Extra thoracic metastasis n (%)
Treatment n (%)
n=number of patients; SD=standard deviation.
Figure 1 - Sixty-month survival Kaplan-Meier curve for NSCLC
patients grouped according to smoking status.
CLINICS 2011;66(11):1873-1877Non-small cell lung cancer in never-smokers
Santoro IL et al.
expected, early disease diagnosis, patient treatment and
higher Karnofsky Performance Status scores were also
favorable, independent predictors of survival. Interes-
tingly, neither female gender nor having adenocarcinoma
reached the specified significance level in the multivariate
survival analyses, although both variables accounted for a
significantly higher proportion of never-smoker patients in
the univariate analysis.
Never-smokers constituted 24% of the NSCLC patients in
our population. The literature supports the assertion that
several characteristics are more commonly seen in NSCLC
patients who are never-smokers. Our study found that
women were more likely than men to have non-smoking-
associated lung cancer (68%). The risk of developing lung
cancer among women who smoke has been described as
higher than that of men who are exposed to the same
smoking rate.13-18These results are still controversial, and
the possibility that women have an increased susceptibility
to the effects of smoking is not yet clearly defined. However,
the predominance of females among never-smokers with
tumors, even without exposure to cigarette smoke carcino-
gens, has been previously described, suggesting that aspects
related to hormonal factors may interfere with tumor
The role of estrogen in the carcinogenesis of other types of
tumors in women is well established. Growing evidence
indicates the effects of estrogen on lung cancer cells. The
presence of estrogen receptors (ERs) in pulmonary tumor
cells suggests that this hormone plays a role in the
carcinogenesis of lung cancer.19-21There are two main types
of ERs in humans: ER-alpha and ER-beta. ER-beta receptors
are the major mediators of estrogen activity in lung cells.
They are active receptors in lung tissue and can contribute
to the growth of neoplastic cells. Although the prevalence of
ERs in tumor cells is similar in men and women, gender
differences in survival exist.22,23The mechanism underlying
these sex-based differences is unclear, but genetic and
metabolic factors, hormonal influences, and the presence of
specific isoforms of ER-beta may be involved.
Another interesting finding is the predominance of
adenocarcinoma among never-smoking patients, which is
Although this histological variant is most commonly found
in women, never-smoking men also showed a higher
proportion of adenocarcinoma in our study, suggesting that
a factor unrelated to sex is responsible for the predominance
of adenocarcinomas in the never-smoking population.
Several genetic alterations have been described that may
contribute to the development of adenocarcinoma in
nonsmokers. Two main pathways for the development of
lung adenocarcinoma have been described: the KRAS and
the epidermal growth factor receptor (EGFR)20pathways.
KRAS mutations are generally linked to tobacco consump-
tion, and the EGFR pathway is generally associated with
nonsmokers.26-28Recent studies have indicated that patients
with mutations in the EGFR gene respond better to
treatment withEGFR tyrosine
Although KRAS mutations are historically considered to
represent a tumorigenic pathway in smokers, their pre-
valence has been reported to be similar in smokers and
nonsmokers; however, differences in mutation type have
been reported.31Though this is still controversial, molecular
differences between groups may be responsible for distinct
clinical manifestations and responses to treatment. As
biomarkers may be used for risk stratification and treatment
selection, new pathogenic pathways are being studied.32,33
In contrast to studies in Asian populations, we did not
find differences in the age of diagnosis among never-
smokers compared with ever-smokers.34Our findings are
consistent with the results of studies performed in Europe
and the United States, where this disease occurs mainly in
older adults. These differences may be explained by the
hypothesis that indoor air pollutants, such as cooking
fumes, play a role in lung carcinogenesis in developing
countries, although there is some controversy surrounding
this issue.35Exposure to cooking fumes is common in Brazil;
however, we lacked information regarding our participants’
exposure levels to such fumes.
As lung cancer is considered a disease of smokers,36,37
never-smoker patients may experience either late presenta-
tion or late diagnosis on the part of physicians. The
majority of our patients presented with the disease at later
stages; however, when the group of never-smokers was
analyzed for gender associations, we found that women
were more likely than men to have lung cancer diagnosed
at a more advanced stage. It is noteworthy that we did not
find differences in extrathoracic disease between never-
smokers and ever-smokers. Consequently, the clinical
threshold for investigating symptomatic never-smokers
must be lower.
The limitations of our study are related to the lack of
information about passive smoking and cooking fume
exposure as well as molecular analyses of the tumors.
However, the epidemiological behavior of our never-
smoker sample confirmed that even a racially varied
population, as found in Brazil, follows the same model as
that of never-smokers in other parts of the world.
In conclusion, the vast majority of never-smoker lung
the predominant histological type. Additionally, the female
Table 3 - Multivariate analysis of factors related to overall survival in 285 NSCLC patients, using Cox regression (-2 log
likelihood=1,265.5; chi-squared=60.0; p,0.001).
Variable CoefficientSE Adjusted HR95% CIp-value
Early disease detection
KPS=Karnofsky Performance Status Scale; SE=standard error; HR=hazard ratio; CI=confidence interval for HR.
# = continuous variable.
Non-small cell lung cancer in never-smokers
Santoro IL et al.
never-smoker patients showed a higher proportion of ad- Download full-text
vanced disease, although the proportion with extrathoracic
metastasis was similar to that of male never-smokers. Among
NSCLC patients, after adjusting for age, female gender and
adenocarcinoma, being a never-smoker with early treatment
of the disease and having a higher Karnofsky Performance
Status Scale were associated with a better prognosis. Lung
cancer in never-smokers has a different clinical profile, with a
distinctly lower mortality rate compared to lung cancer
among smokers, which reflects a singular clinical behavior
and natural history.
Financial disclosure: Prof. Ilka Lopes Santoro and Dr.
Se ´rgio Jamnik are coinvestigators in a Phase III research
project supported by AstraZe ˆnecaH, BoehringerH, AbbottH
and BristolH. They are also involved in a Phase II project
supported by Merck Sharp DomeH.
The other authors do not have any financial disclosures to
Santoro IL and Fernandes ALG conceived and designed the study, were
responsible for the analysis and interpretation of the data, critical revision,
and final approval. Ramos RP, Franceschini J, and Jamnik S were
responsible for the collection, analysis and interpretation of data, and draft
of the article.
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CLINICS 2011;66(11):1873-1877 Non-small cell lung cancer in never-smokers
Santoro IL et al.